RESEARCH AND RELATED OTHER PROJECT INFORMATION - PROJECT SUMMARY / ABSTRACT Funding Opportunity: PA-18-574 - PI Name: Mamet, Julien As described by the HEAL Initiative Notice NOT-NS-19-014, there currently exists an urgent unmet need for enhanced pain management in the form of safe, effective, non-opioid pain treatments. Chronic focal neuropathic pain, which includes pain etiologies such as radiculopathy and radiculitis1-3, focal peripheral neuropathies4, and low back pain5, affects as many as 25 million patients annually in the United States. These conditions are commonly treated with opioid analgesics, with some patients subsequently experiencing addiction and abuse. Chronic focal neuropathic pain is maintained by genome-wide transcription regulation in the dorsal root ganglia (DRG) / spinal cord network. The transcription factors driving this regulation constitute a promising class of targets with the potential to alter the course of pain with a single treatment. DNA decoys are oligonucleotides that specifically inhibit the activity of certain transcription factors. Following advancement of Adynxx?s lead decoy program, brivoligide (formerly AYX1) the for treatment postoperative pain, into Phase 2 clinical studies, Adynxx began development of its second decoy AYX2 for altering the course of chronic pain. AYX2 binds and inhibits Krppel-like transcription factors (KLF) 6, 9 and 15 in the DRG-spinal cord. In the Spared Nerve Injury and Chronic Constriction Injury rat models of chronic pain, a single intrathecal (IT) injection of AYX2 produces a substantial, weeks-long reduction of pain compared to controls.6 The goal of this Phase 1 proposal is to advance AYX2 toward an IND submission, allowing for human clinical trials. We propose in Aim 1 to characterize AYX2 pharmacokinetics in the cerebrospinal fluid and plasma and its distribution in the DRG, spinal cord and brain following an IT injection. With this information, AYX2 will be tested in a panel of complementary toxicology studies in Aim 2 to allow for final IND-enabling studies, supported by Phase 2 of the grant. This research will accelerate development of AYX2 as a novel drug candidate for the non-opioid treatment of pain.